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Rational drug combinations with CDK4/6 inhibitors in acute lymphoblastic leukemia
- Source :
- Haematologica, Vol 107, Iss 8 (2021)
- Publication Year :
- 2021
- Publisher :
- Ferrata Storti Foundation, 2021.
-
Abstract
- Despite improvements in outcomes for children with B- and T-cell acute lymphoblastic leukemia (B-ALL and T-ALL), patients with resistant or relapsed disease fare poorly. Previous studies have demonstrated the essential role of cyclin D3 in T-ALL disease initiation and progression and that targeting of the CDK4/6-cyclin D complex can suppress T-ALL proliferation, leading to efficient cell death in animal models. Studies in leukemia and other malignancies, suggest that schedule is important when combining CDK4/6 inhibitors (CDKi) with cytotoxic agents. Based on these observations, we broadened evaluation of two CDKi, palbociclib (PD-0332991, Pfizer) and ribociclib (LEE011, Novartis) in B- and T-ALL as single agent and in combination with conventional cytotoxic chemotherapy, using different schedules in preclinical models. As monotherapy, CDKi caused cell cycle arrest with a significant decrease in S phase entry and were active in vivo across a broad number of patient-derived xenograft samples. Prolonged monotherapy induces resistance, for which we identified a potential novel mechanism using transcriptome profiling. Importantly, simultaneous but not sequential treatment of CDKi with conventional chemotherapy (dexamethasone, L-asparaginase and vincristine) led to improved efficacy compared to monotherapy in vivo. We provide novel evidence that combining CDKi and conventional chemotherapy can be safe and effective. These results led to the rational design of a clinical trial.
- Subjects :
- Diseases of the blood and blood-forming organs
RC633-647.5
Subjects
Details
- Language :
- English
- ISSN :
- 03906078 and 15928721
- Volume :
- 107
- Issue :
- 8
- Database :
- Directory of Open Access Journals
- Journal :
- Haematologica
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.5de625346f4e411da1839face46afb2f
- Document Type :
- article
- Full Text :
- https://doi.org/10.3324/haematol.2021.279410